Standard treatments for cancer vary depending on type of cancer, stage and location. For local disease, excision and/or radiation may be used. For systemic disease, chemotherapy may be used, and for hormone-dependent tumours, hormone ablation therapy is an option. With the exception of surgery, treatment success is limited by toxicity and resistance.
Research during the past decade has identified several proteins that may promote progression and resistance by inhibiting apoptosis. Of special relevance to development of AI (androgen-independent) progression and hormone refractory prostate cancer (HRPC) are those survival proteins that are up-regulated after apoptotic triggers, such as androgen ablation, that function to inhibit cell death.
Clusterin is a ubiquitous protein with a diverse range of proposed activities. In prostate epithelial cells, expression of clusterin increases immediately following castration, reaching peak levels in rat prostate cells at 3 to 4 days post castration, coincident with the onset of massive cell death. These results have led some researchers to the conclusion that clusterin is a marker for cell death, and a promoter of apoptosis. On the other hand, it has been observed that Sertoli cells and some epithelial cells express high levels of clusterin without increased levels of cell death. In Sensibar et al., Cancer Research 55: 2431-2437, 1995, the authors reported on LNCaP cells transfected with a gene encoding clusterin, and watched to see if expression of this protein altered the effects of tumor necrosis factor α (TNFα), to which LNCaP cells are very sensitive. Treatment of the transfected LNCaP cells with TNFα was shown to result in a transient increase in clusterin levels for a period of a few hours, but these levels had dissipated by the time DNA fragmentation preceding cell death was observed.
Clusterin is expressed in a number of tumour types including breast (Redondo, M.; Villar, E.; Torres-Munoz, J., et al. Am J Pathol (2000) 157(2):393-9), non-small cell lung carcinoma (July, L. V.; Beraldi, E.; So, A. et al. Mol Cancer Ther (2004) 3(3):223-32.), prostate (Miyake, H.; Nelson, C.: Rennie, P. S.; et al. Cancer Res. (2000) 60(1):170-6), ovarian (Hough, C. D.; Cho, K. R.; Zonderman A. B. et al. Cancer Res. (2001) 61(10):3869-76), renal, and bladder (Miyake, H.; Gleave, M.; Kamidono, S.; Urology (2002) 59(1): 150-4).
Transfection studies in vivo result in the development of a phenotype that is resistant to standard therapies. Inhibition studies result in delay in progression and the promotion of apoptosis, as well as in increased chemotherapy and radiation therapy sensitivity.
Antisense treatment of cancer is still a relatively new science. Certain aspects such as optimal dosing and route of administration are still a matter of study (Gewirtz, A. M. Curr Opin Mol Ther. (1999) 1(3):297-306; and Dean, N. M.; Bennett, C. F.; Oncogene (2003) 22(56):9087-96). Continuous infusion is a requirement of the first generation of antisense therapeutics, which are characterized by rapid clearance from plasma and do not show significant pooling in target tissue. The antisense therapeutics thus administered may not accumulate in target tissues sufficiently to down-regulate the genetic and/protein targets, particularly in solid tumours.
There is a need for therapies that have better tissue pharmacokinetics so that less frequent and inconvenient administration is required. Also, efficient delivery will reduce the risk of unwanted side effects and potential toxicities. Effective systemic therapies must therefore have excellent biodistribution to tumour sites, lymph nodes, and other common sites of metastases, to afford optimal treatment.
PCT Publication WO 00/049937 and PCT Publication WO 03/072591, which are incorporated herein by reference, describe the use of antisense therapy which reduces the expression of clusterin in certain cancers.